Neural peptidase endothelin-converting enzyme 1-regulates endothelin induced pruritus

2014 | journal article. A publication with affiliation to the University of Göttingen.

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​Neural peptidase endothelin-converting enzyme 1-regulates endothelin induced pruritus​
Kido-Nakahara, M.; Buddenkotte, J.; Kempkes, C.; Ikoma, A.; Cevikbas, F.; Akiyama, T. & Nunes, F. et al.​ (2014) 
Journal of Clinical Investigation124(6) pp. 2683​-2695​.​ DOI: https://doi.org/10.1172/JCI67323 

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Authors
Kido-Nakahara, Makiko; Buddenkotte, Joerg; Kempkes, Cordula; Ikoma, Akihiko; Cevikbas, Ferda; Akiyama, Tasuku; Nunes, Frank; Seeliger, Stephan; Hasdemir, Burcu; Mess, Christian; Buhl, Timo; Sulk, Mathias; Mueller, Frank-Ulrich; Metze, Dieter; Bunnett, Nigel W.; Bhargava, Aditi; Carstens, Earl; Furue, Masutaka; Steinhoff, Martin
Abstract
In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.
Issue Date
2014
Status
published
Publisher
Amer Soc Clinical Investigation Inc
Journal
Journal of Clinical Investigation 
ISSN
1558-8238; 0021-9738

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